In U.S. Pat. No. 4,738,971 some derivatives of N-aryl-1,2-dihydro-4-substituted-1-alkyl-2-oxo-quinoline-3-carboxamide are claimed as enhancers of cell-mediated immunity. Said patent discloses four methods for the preparation of the compounds. According to the method closest to that of the present invention, the compounds are prepared by reacting a carboxylic acid or a reactive derivative thereof with an amine or reactive derivative thereof in the presence of pyridine or quinoline as an inert solvent. U.S. Pat. No. 5,912,349 discloses an improved process to produce one of these compounds, roquinimex (Merck Index 12th Ed., No. 8418; Linomide®, LS2616, N-phenyl-N-methyl-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-quinoline-3-carboxamide). In said patent, a reaction between N-methylisatoic anhydride and N-methyl-N-phenyl-α-carbomethoxyacetamide gives the desired compound. U.S. Pat. Nos. 6,077,851, 6,133,285 and 6,121,287 disclose the preparation of quinoline-3-carboxamide derivatives. The derivatives may be prepared by various known methods, for example, by reaction of a quinoline-3-carboxylic acid ester derivative with an aniline in a suitable solvent such as toluene, xylene and the like. In the examples disclosed, wherein toluene is used as a solvent, the yields are ≦80%.
The prior art N-acylation reaction below
showing the N-acylation reaction conducted with a quinoline-3-carboxylic acid ester derivative has now been found to be an equilibrium reaction where the equilibrium point unexpectedly lies far to the left. An illustrative example is provided by heating a quinoline-3-carboxamide derivative (compound C), for example, wherein R5=chloro and R6=H, R=ethyl and R′=R″=hydrogen, in a sealed vessel at 100° C. with one equivalent of methanol in toluene as a solvent. An almost complete transformation into the corresponding methyl ester (compound A) results after less than 30 minutes.
The chemical stability of the desired product is such that degradation occurs under the reaction conditions.

Degradation of a quinoline-3-carboxamide derivative.
An illustrative example is provided above. The degradation product (compound F) is the decarboxylated quinoline-3-carboxylic acid (compound E). Compound E is formed from the reaction between the quinoline-3-carboxamide derivative and water. It is unavoidable that small amounts of water exist in a reaction mixture. Small amounts of water are always present in the starting materials and in the solvent, and water can also enter the reaction mixture during the reaction. When using, for example, toluene, the desired product is dissolved and prone to reaction with water. The quinoline-3-carboxylic acid that is formed in the reaction between the quinoline-3-carboxamide derivative and water undergoes a decarboxylation reaction to yield the decarboxylated product (compound F). The quinoline-3-carboxylic acid is not present in the crude product in a detectable amount. The quinoline-3-carboxylic acid ester (compound A) also undergoes a similar reaction with water but at a much slower rate.